A Chemical-Genetic Approach Reveals the Distinct Roles of GSK3alpha and GSK3beta in Regulating Embryonic Stem Cell Fate.

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Publication Year:
2017
Authors:
Xi Chen, Ruizhe Wang, Xu Liu, Yongming Wu, Tao Zhou, Yujia Yang, Andrew Perez, Ying-Chu Chen, Liang Hu, Jean Paul Chadarevian, Amir Assadieskandar, Chao Zhang, Qi-Long Ying
PubMed ID:
29207259
Funding Grants:
Public Summary:
Glycogen synthase kinase 3 (GSK3) plays a central role in diverse cellular processes. GSK3 has two mammalian isozymes, GSK3alpha and GSK3beta, whose functions remain ill-defined because of a lack of inhibitors that can distinguish between the two highly homologous isozymes. Here, we show that GSK3alpha and GSK3beta can be selectively inhibited in mouse embryonic stem cells (ESCs) using a chemical-genetic approach. Selective inhibition of GSK3beta is sufficient to maintain mouse ESC self-renewal, whereas GSK3alpha inhibition promotes mouse ESC differentiation toward neural lineages. Genome-wide transcriptional analysis reveals that GSK3alpha and GSK3beta have distinct sets of downstream targets. Furthermore, selective inhibition of individual GSK3 isozymes yields distinct phenotypes from gene deletion, highlighting the power of the chemical-genetic approach in dissecting kinase catalytic functions from the protein's scaffolding functions. Our study opens new avenues for defining GSK3 isozyme-specific functions in various cellular processes.
Scientific Abstract:
Glycogen synthase kinase 3 (GSK3) plays a central role in diverse cellular processes. GSK3 has two mammalian isozymes, GSK3alpha and GSK3beta, whose functions remain ill-defined because of a lack of inhibitors that can distinguish between the two highly homologous isozymes. Here, we show that GSK3alpha and GSK3beta can be selectively inhibited in mouse embryonic stem cells (ESCs) using a chemical-genetic approach. Selective inhibition of GSK3beta is sufficient to maintain mouse ESC self-renewal, whereas GSK3alpha inhibition promotes mouse ESC differentiation toward neural lineages. Genome-wide transcriptional analysis reveals that GSK3alpha and GSK3beta have distinct sets of downstream targets. Furthermore, selective inhibition of individual GSK3 isozymes yields distinct phenotypes from gene deletion, highlighting the power of the chemical-genetic approach in dissecting kinase catalytic functions from the protein's scaffolding functions. Our study opens new avenues for defining GSK3 isozyme-specific functions in various cellular processes.